Cyclobutanones, substituted synthesis

The base-induced ring contraction of cyclobutanones substituted with a leaving group in the a-position is now a well-established procedure for the synthesis of cyclo-propylcarbonyl compounds. This reaction has now been extended to include 2-... 

An attractive synthesis of cyclobutanone (253) has been recently described using 1-isocyano-l-tosylcyclobutane(252)(equation 151)144. l-Isocyano-l-tosylcyclobutanes252 can be prepared from (tosylmethyl)isocyanide and alkyl-substituted 1,3-dibromobutanes. This method appears to be superior to previously reported methods for the preparation of cyclobutanone because of high purity and high yields. 

In a projected synthesis of verrucarol in which the tetrahydropyranone 175 is envisioned to play a role, the lactone 176 can serve as a viable intermediate (Scheme 6)7S>. Using cyclobutanone annulation methodology, 177 becomes the required intermediate. The geminal substitution of 177 can also be recognized to derive from a spiroannulation approach as previously analyzed. 

This modification of the Curtius reaction has been used extensively in many laboratories and has been found to be generally applicable. Some examples from the literature include the stereoselective synthesis of a wide variety of cyclopropylamine derivatives from the corresponding acids,11-13 the stereoselective preparation of some substituted norbornylamines from easily isomerized acids,14 the preparation of some 1-aminocyelobutancearboxylic acids from the corresponding acid esters,18 the preparation of a substituted cyclobutanone from... 

Ketene acetals and thioacetals can be used as ketene equivalents in cyclobutanone synthesis in situations where ketene to alkene cycloadditions are inefficient such as in the case of electron-deficient alkenes.14 Although thermal cycloadditions of ketene acetals and thioacetals with electron-deficient alkenes have been observed (see Section 1,3.2.1.), such cycloadditions proceed more efficiently and under milder conditions with metal catalysts. Efficient cycloadditions between ketene dimethyl acetal and alkenes substituted by a single electron-withdrawing group have been reported.15... 

The homopropargyl rearrangement is of preparative interest for the synthesis of cyclobu-tanone and substituted cyclobutanones (Table 3). For example, the rearrangement of 4-(triflu-oromethanesulfonyloxy)but-l-yne (4) takes place almost quantitatively (76% conversion) in the presence of trifluoroacetic acid and sodium trifluoroacetate to produce cyclobutanone.6... 

Both the Baeyer-Villiger and the Beckmann rearrangement are used on the cyclobutanones formed in these cycloadditions. Dechlorination of adduct 12 with zinc and rearrangement with a peroxy-acid gives a lactone 25 widely used in prostaglandin synthesis.5 Note that the more substituted carbon migrates and does so with retention of configuration. 

The key synthetic steps in the formation of the desired unnatural amino acids, 5-8, involved the preparation of appropriately substituted cyclobutanones followed by a Btlcherer-Strecker amino acid synthesis.12 The syntheses of the boron-containing amino acids were initiated utlizing alkenes 16 -19. Alkene 17 was prepared by a SN2 displacement of bromide from 4-bromobenzyl bromide (Scheme 3). In the syntheses of alkenes 18 and 19, a catalytic... 

Cycloadditions of ketenes with alkenes and alkynes constitute the most popular method for the synthesis of cyclobutanones and cyclobutenones. Unfoitunately, however, this process is truly general only for highly nucleophilic ketenophiles such as conjugated dienes and enol ethers. In general, unactivated alkenes and alkynes fail to react in good yield with either alkyl- or aryl-substituted ketenes, or with ketene itself To circumvent this limitation, dichloroketene is usually employed as a ketene equivalent, since this electrophilic ketene reacts well with many types of unactivated multiple bonds, and the resultant cycloadducts undergo facile dechlorination under mild conditions. ... 

Regio problems can arise if aromatic ketones are involved in the cyclobutanone synthesis, and aldehydes can only be forged into the cyclobutanone skeleton by detouring via methylthio-substituted cyclopropanes (equation 130) ... 

In general, cyclobutanones are synthesized by either ketene cycloadditions or by ring expansions of cyclopropyl precursors. For the synthesis of simple a-substituted monocyclic cyclobutanones, the latter method is usually employed, and a variety of approaches have been used to prepare the required eyclopropyl intermediates. 

There are several advantages to the procedure described here for the synthesis of a-substituted cyclobutanones. The preparation of 1-bromo-l-ethoxycyclopropane is convenient and can be accomplished in good overall yield in only two steps from commercially available ethyl 3-chloroprop1onate. Hetalation of 1-bromo-l-ethoxycyclopropane is rapid and reproducible on a large scale and (l-ethoxy)cyclopropyllithium adds cleanly to a wide variety of... 

Trost also found that treatment of these cyclobutanones with sodium methoxide and diphenyl disulfide leads to in situ bisulfenylation and ring cleavage (secosulfenylation). This was applied to the total synthesis of verrucarol, a complex tetrahydrochromanone substituted at the ring junction by a hydroxymethyl substituent. The synthetic strategy twice used the cyclobutanone formation from 1-lithiocyclo-propyl phenyl sulfide and a ketone, followed by the secosulfenylation process and Baeyer-Villiger type rearrangement of cyclobutanone. Only this part of the synthesis is described in Scheme 28. 

Finally, l-(l -hy(boxyalkyl)-l-(methylseleno)cyclopropanes and some rare phenylseleno analogs belonging to the phenylct inol series produce cyclobutanones on reaction with p-toluenesulfonic acid in a similar manner to the phenylthio analogs. This reaction has allowed the synthesis of a large variety of cyclobutanones, induing those that are polyalkylated (Scheme 163 f ),J2.77.>s9.> ),i99 ajyj substituted or vinyl substituted (Scheme 132, a Scheme 186), by selective migration of the more-substituted carbon (Scheme 163, compare h with f).i2.77,i60... 

Lawlor, M. D., Lee, T. W., Danheiser, R. L. Rhodium-Catalyzed Rearrangement of a-Diazo Thiol Esters to Thio-Substituted Ketenes. Application in the Synthesis of Cyclobutanones, Cyclobutenones, and 3-Lactams. J. Org. Chem. 2000, 65, 4375-4384. 

It is well known that cyclobutanones can be transformed to cyclopentane derivatives directly with diazomethane or indirectly via the cyanohydrins218> 228), or with tris(phe-nylthio)methyllithium 219,220), but in many cases the reactions are not regioselective and lead to different regioisomers. Cyclobutyl ketones lead to substituted cyclopentanones in highly acidic media 226 and the synthesis of cyclopentanones from methylene-cyclobutanes requires a palladium catalyst 227). 

The Wolff rearrangement of six- and five-membered a-diazocycloalkanones has been extensively applied to the synthesis of highly strained frameworks. The rearrangement of an (x-diazo-cyclobutanone was reported from 2-diazo-3,4-bis(diphenylmethylene)cyclobutanone (1). The diazo ketone (1) was prepared by treatment of the 3,4-bis(diphenylmethyl-ene)cyclobutane-l,2-dione tosylhydrazone with alumina in 95% overall yield from the corresponding cyclobutanedione. Irradiation in the presence of water, alcohols and aniline afforded 1-carboxy-, 1-alkoxycarbonyl- and 1-phenylcarbamoyl-substituted 2,3-bis(diphenyl-methylene)cyclopropanes 2, respectively, in 13-87% yields. Thermal decomposition in aqueous dioxane afforded the cyclopropanecarboxylic acid 2 (X = OH) in 52% yield. ... 

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